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Home , Alexander disease, Batten disease, Canavan disease, Krabbe disease, Zellweger syndrome

Lysosomes, and Mitochondria: Function and Disorder

Laurence E. Becker1

From the Department of Pathology (Neuropathology), University of Toronto and The Hospital for Sick Children, Toronto, Ontario, Canada

Enzyme defects localized to lysosomes, mito­ disorders require further biochemical clarification. chondria, and peroxisomes produce significant Neonatal ALD and Zellweger syndrome are ex­ neurologic . affecting primarily amples of well-defined diseases produced by per­ gray matter are largely due to defects of oxisomal enzyme defects. Many other metabolic lysosomes producing disruption of catabolic diseases are associated with neurological mani­ pathways and storage within of , festations without evidence of abnormal neuroim­ carbohydrate, mucopolysaccharide, or glycogen. The degree of metabolic product accumulation, aging or gross neuropathology. The emphasis of the specificity of cell type, anatomic localization this chapter is on patterns of pathology in the of neuronal involvement, and maturation level of metabolically better defined diseases in order to the determine the nature of the neuropath­ provide the basis for correlation with neuroim­ ology. From this heterogenous group, specific aging. diseases have been selected to illustrate charac­ teristic patterns of pathology. Metabolic diseases affecting primarily are the leukodys­ trophies. The metabolically defined leukodystro­ Introduction phies now include metachromatic leukodystro­ phy, , The spectrum of disorders caused by a meta­ (ALD), , and Pelizaeus-Merz­ bolic abnormality is wide (1, 2), Most inherited bacher disease. However, other metabolic diseases are related to enzyme defects are also included in the differential diagnosis: within lysosomes, but recent advances emphasize , , sudan­ abnormalities of mitochondria and peroxisomes. ophilic . Metabolic disorders that Understanding the role that organelle pathology affect gray and white matter to approximately plays in the pathogenesis of muscle, , neu­ the same extent include diseases whose enzy­ ron, oligodendroglia, or disturbance is matic defects have been localized to mitochondria essential for the elucidation of metabolic disorders or peroxisomes. Apart from Leigh encephalop­ (1). Abnormality of organelles leads to cellular athy and focal cerebral ischemic lesions, the pat­ dysfunction and organ failure. It is the abnormal terns of pathology associated with disorders of mitochondrial have not been established organ that imaging modalities can identify. In the with a significant degree of certainty due to the brain, patterns of pathology can be recognized, evolving understanding of the molecular biology but these patterns are complicated by the differ­ of these conditions. Similarly, many peroxisomal ing stages of the disease and the age of the child. In broad general terms, four patterns of patho­ logic involvement emerge: involvement primarily 1 Address reprint requests to Dr L. E. Becker, Department of Pathol­ ogy, The Hospital for Sick Children, 555 University Avenue, Toronto, of gray matter, involvement primarily of white Ontario, Canada M5G 1X 8. matter, involvement of both gray and white mat­

Index terms: Brain, diseases; Brain, metabolism; Pediatric neuroradiology. ter, and no recognizable involvement of either

AJNR 13:609-620, Mar/ Apr 1992 0195-6108/92/ 1302-0609 gray or white matter (no recognizable gross neu­ © American Society of Neuroradiology ropathology). 609 610 AJNR: 13, March/ April 1992

Metabolic Diseases Affecting Primarily Gray Lipidoses Matter The lipid storage diseases are rare. Some have Those disorders that primarily affect gray mat­ an identified enzyme defect, such as absence of ter are largely due to lysosomal enzyme defects. hexosaminidase in Tay-Sachs disease, and others Lysosomal enzymes are synthesized in the cyto­ have no detectable enzyme defect, such as the plasm and transported into the cisternae of the group of neuronal ceroid lipofuscinosis. In Tay endoplasmic reticulum where they are packaged Sachs disease for example, GM2 ac­ cumulates in neurons without demonstrable se­ into primary lysosomes by the Golgi apparatus. lectivity for any particular group of neurons. In Fusion with autophagic vacuoles creates second­ the early stages of Tay Sachs, there may be ary lysosomes where the enzymes (hydrolases) (3) due to ganglioside storage. degrade the contents of the autophagic vacuoles As the ganglioside interferes with intracellular (1) . The lysosomes are the garberators of the cell. function, the neurons begin to crumble (4). The In lysosomal storage diseases, there are deficien­ consequence of neuronal deterioration and death cies of specific catabolic enzymes that result in is cortical atrophy with widened sulci, narrowed the accumulation of undigested material (Table gyri, and dilated ventricles. The optic and 1). This product, usually lipid, carbohydrate, or are also atrophic, since part of the mucopolysaccharide, interferes with cell function neuronal death is axonal deterioration and sec­ resulting in the eventual death of these abnormal ondary demyelination. Secondary demyelination cells. The affected organs or cell types within may be prominent and can be confused with them will be disturbed by the disruption of spe­ diseases that produce primary demyelination, cific metabolic pathways characteristic of the such as the leukodystrophies. target cells. The gross manifestation of these Most of the lipidoses are diagnosed by enzy­ metabolic abnormalities will depend on the cells matic assay in white blood cells. The group of affected. Most often the brain becomes atrophic ceroid lipofuscinosis, of which is with disorders of lysosomal function. one example, cannot be diagnosed enzymatically. Diagnosis is based, instead, on electron micro­ scopic identification of characteristic curvilinear TABLE 1: Lysosomal disorders or fingerprint inclusions found in white blood cells, or skin, or conjunctival biopsy (5). In Batten Storage diseases Lipidoses disease, brain atrophy may be present but it is Gaucher disease mild and white matter changes are absent. Batten Nieman n-Pick disease disease is a progressive childhood disorder oc­ curring between 5 and 10 years of age, associated GM 1 with blindness followed by mental deterioration, GM2 Gangliosidosis (Tay-Sachs) Neuronal ceroid lipofuscinosis , , and myoclonus. Haltia Sa ntavouri disease Jansky-Bielschowsky disease Batten disease Mucopolysaccharidoses Mucopolysaccharidoses I Hurler /Scheie (formerly V) The accumulation of mucopolysaccharides II Hunter (glycosaminoglycans) due to specific enzyme de­ Ill Sanfilippo fects in their catabolism produces six well-rec­ IV Morquio ognized syndromes (Table 1) that are described VI Maroteaux Lamy VII Sly in detail in textbooks of neuropathology (2). The Mucolipidoses enzymatic defects are related to failure to break­ I-IV Mucolipidoses down dermatan sulfate, heparan sulfate, or ker­ Mannosidosis atan sulfate. Although varying widely in severity, Fucosidosis Glycogeneses characteristic features are coarse facial appear­ II Pompe disease ance (gargoylism), some degree of skeletal man­ ifestation (dysostosis multiplex), and multiple or­ Leukodystrophies gan involvement. All the disorders except Mor­ Metachromatic leukodystrophy quio have dysostosis multiplex. is Krabbe leukodystrophy present in all except Scheie syndrome. AJNR: 13, March/ Apri11992 611

Hurler syndrome is the prototypical muco­ with lipid breakdown. Examples of the mucolipi­ polysaccharide storage disease in which there is doses include I cell disease, fucosidosis, and man­ a severe progression of disease leading to death nosidosis. The brain in these disorders is grossly by about 10 years of age. The children have short normal (2). necks, progressive kyphosis, protuberant abdo­ mens, hepatosplenomegaly, and umbilical and inguinal hernias. Mental retardation is a promi­ Glycogen Storage Disease nent feature of Hurler syndrome. Gross exami­ nation of the brain of such a patient reveals This is a heterogeneous group of disorders boggy, fluid-filled, opaque, and thickened men­ associated with deficiencies of enzymes involved inges covering an atrophic cerebrum. The dura in glycogen storage, synthesis, and degradation. surrounding the brain may also be thickened to Patients with glycogen storage disease can pre­ as much as 5 mm. On coronal sectioning, the sent with dysfunction of the liver, heart, muscle, ventricles are large (Figs. 1A and 18). The peri­ or . Pompe disease is one glyco­ vascular spaces are grossly enlarged by accu­ gen storage disease that affects both the central mulation of mucopolysaccharide-containing his­ nervous system (CNS) and muscle (2). Several tiocytes surrounding the blood vessels, particu­ forms of Pompe disease occur at different ages. larly in the centrum semiovale. In Hurler disease, The classic infantile form is associated with hy­ cortical and cerebellar neurons are strikingly bal­ potonia, macroglossia, cardiomegaly, cardiac fail­ looned with lesser involvement of neurons in the ure, and death by 1 year of age. In this form, the brain stem. Electron microscopic studies show brain may be grossly normal, although, histolog­ large intralysosomal accumulations of ganglio­ ically, the neurons are markedly distended by side, but little recognizable mucopolysaccharide. accumulation of glycogen within lysosomes. Gly­ The lysosomal a-1-iduronidase deficiency pro­ cogen is present in many different types of neu­ duces mucopolysaccharide storage that interferes rons but is most prominent in the dorsal root with ganglioside catabolism, resulting in promi­ ganglia, anterior horn cells, and motor nuclei of nent lipid accumulation within neurons (6). These the brain stem. In later stages of Pompe disease, neurons eventually degenerate, so brain atrophy mild cortical atrophy may be discernible. becomes apparent.

Mucolipidoses "Hypoxic-Ischemic" Encephalopathy The mucolipidoses are a group of disorders Particular metabolic disorders, such as those that are associated with accumulation of both associated with defects of enzymes in the urea mucopolysaccharide and within lysosomes cycle and those producing metabolic acidosis and as a result of a single enzyme defect affecting hypoglycemia, may be associated with a pattern both catabolic pathways. This situation is differ­ of hypoxic-ischemic encephalopathy with exten­ ent from that in mucopolysaccharidoses, where sive neuronal loss and manifesting as the accumulating mucopolysaccharide interferes cortical atrophy.

Fig. 1. Hurler disease; coronal views of specimen. Mucopolysaccharide deposition significantly enlarges the Virchow-Robin spaces. A, occipital, mild; B, frontal, severe. 612 AJNR: 13, March/Apri11992

Metabolic Diseases Affecting Primarily White tern with sparing of U fibers (Fig. 2), diffuse Matter (Leukodystrophies) margins, and involvement of the cerebellum. Metachromatic leukodystrophy is associated Traditionally, diseases affecting white matter with a deficiency of arylsulfatase-A. Defects of have been divided into the categories of myeli­ this catabolic enzyme result in failure of the noclastic and dysmyelinating (7). In myelinoclas­ to be properly broken down and reutilized, tic diseases, the myelin sheath is intrinsically resulting in accumulation of . normal until it later succumbs to endogenous or Disorders of arylsulfatase-A deficiency have been exogenous myelinotoxic factors. Viral demyeli­ classified on the basis of clinical manifestations nating diseases include subacute sclerosing pan­ into late infantile, juvenile, and adult groups. encephalitis (measles), subacute sclerosing ru­ The most common is the late infantile form bella panencephalitis, progressive multifocal leu­ that presents between 1 and 2 years of age with koencephalopathy (papova), and demyelination motor signs of followed by associated with HIV infection. Postinfectious de­ deterioration in intellect, speech, and coordina­ myelination, methotrexate/irradiation-induced tion. Within 2 years of onset, there is evidence of demyelination, and also belong severe white matter dysfunction: quadriplegia, to the myelinoclastic category. blindness, and decerebrate posturing. The brain From a metabolic perspective, the interest is tends to be atrophic and the ventricles dilated. in dysmyelinating diseases where an intrinsic (in­ The white matter takes on a dull, chalky, white herited) enzyme deficiency results in disturbed formation, destruction, or turnover of essential components of myelin. Not discussed in this TABLE 2: Leukodystrophies presentation are metabolic diseases with focal Name Distinguishing Gross Characteristics

demyelination: cerebrotendinous xanthomatosis, Metachromatic LD Bassen-Kornzweig syndrome, and aminoacidurias Krabbe disease Fine calcification of basal ganglia (maple syrup urine disease, phenylketonuria) (2). Adrenal LD Severe loss of myelin In myelinoclastic demyelination, the pattern of Occipital then frontal involvement damage lacks symmetry. The lesions are sharply Alexander disease Large brain Frontal then occipital involvement demarcated, irregularly involve subcortical ar­ Periventricular contrast enhancement cuate or (]fibers, and tend to spare the cerebellar Canavan disease Large brain white matter. In contrast, in dysmyelination, the Subcortical arcuate fibers selectively involved pattern of abnormal myelination is symmetrical Pelizaeus-Merzbacher LD Leopard skin demyelination in both hemispheres, tends to have diffuse mar­ Cockayne syndrome Leopard skin demyelination Large deposits of calcium, basal ganglia and gins, spares the (]fibers, and consistently involves centrum ovale the cerebellar white matter. Sudanophilic LD The leukodystrophies are a heterogeneous Others group of diseases that have in common extensive Note.-LD =leukodystrophy. degenerative changes within CNS white matter. They are sometimes referred to as dysmyelinat­ ing disorders (Table 2). As biochemical abnor­ malities are identified, the leukodystrophies be­ come more accurately classified. Those disorders with defined biochemical abnormalities include metachromatic leukodystrophy, Krabbe disease, ALD, Canavan disease, and Pelizaeus-Merzbacher disease. Dysmyelination disorders in which the enzyme defects have not been determined are characterized largely by clinico-pathologic obser­ vations, ie, Alexander disease, Cockayne disease, and sudanophilic leukodystrophy.

Metachromatic Leukodystrophy

In metachromatic leukodystrophy, the pattern Fig. 2. Metachromatic leukodystrophy. Coronal section with of demyelination is a classical symmetrical pat- symmetrical demyelination and sparing of U fibers. AJNR: 13, March/April1992 613 to gray color. The cerebellum is often small and In severely affected areas, the white matter may firm with atrophy of the folia. be a fibrous mesh with occasional small cystic Histologically, axonal damage and loss are usu­ areas. The cerebellar white matter is also affected, ally severe in demyelinated areas. Astrogliosis is but to a lesser degree. prominent in areas of demyelination. Within the The histologic features are typical, showing a white matter are numerous granular bodies that prominent loss of myelin with astrogliosis, and are clearly metachromatic and represent the ac­ the diagnostic accumulation of clusters of globoid cumulation of the sulfatide. In the juvenile and and epithelioid cells present throughout the areas adult forms, the metachromatic sulfatide also of demyelination. accumulates within neurons, producing both de­ myelination and modest neuronal storage (8). Adrenoleukodystrophy The pattern of demyelination in classical ALD Krabbe Disease is similar to metachromatic and Krabbe leuko­ The pattern of demyelination in Krabbe disease dystrophy, except that the demyelination is more is one of classic dysmyelination (Fig. 3). severe with early and prominent occipital involve­ Clinical onset in Krabbe disease is early, be­ ment (Figs. 4A and 4B). ALD is inherited as an tween 3 and 5 months of age, usually associated X-linked condition and manifests in four clinical with intermittent , seizures, feeding prob­ forms (11): classical ALD, adrenomyeloneuropa­ lems, hyperirritability, and, eventually, psycho­ thy, neonatal ALD, and symptomatic heterozy­ motor regression. Death usually occurs by 2 years gotes. Because of confusion and inappropriate of age. Finely stippled deposits of calcium are application of the term Shilder disease, it is best present in the basal ganglia and can be demon­ avoided (1). In classical ALD, symptoms usually strated by computed tomography (CT) (9). The begin in the first decade of life. The course is defect in Krabbe disease is a deficiency of lyso­ somewhat prolonged with death occurring be­ somal I ( 10). tween 1 and 9 years after onset. Relapsing and In affected patients, the brain is small with remitting courses have been reported. Behavioral evidence of . The sectioned ce­ disturbances are the most frequent initial pres­ rebrum has the typical appearance of leukodys­ entation, leading to seizures, visual loss, cortico­ trophy with discoloration of the centrum ovale spinal tract involvement, and, eventually, spastic and corona radiata and preservation of the sub­ quadraparesis. The biochemical abnormality is cortical arcuate fibers. The ventricles are dilated. the accumulation of very long chain fatty acids that are normally degraded in peroxisomes (12, 13). At autopsy, there is usually evidence of cere­ bral atrophy and ventricular dilatation. However, the cerebral cortex is normal and the abnormali­ ties are restricted to white matter. In the early phases of the disease, the changes are most severe in the occipital regions. As the disease progresses, the demyelination moves from the occipital to the parietal and posterior temporal lobes. These regions are firm and appear gelati­ nous and brown in the unfixed state. The demye­ lination is extensive and very complete compared to some of the other leukodystrophies where there are some small areas of myelin preserva­ tion. The demyelination tends to be symmetrical posteriorly but is asymmetrical in the frontal lobes. Secondary degeneration of the corticospi­ nal tracts causes a gray, shrunken appearance of the posterior limb of the internal capsule, the Fig. 3. Krabbe disease. Coronal section with symmetrical de­ myelination indicated by diminished blue staining. The ventricles cerebral peduncles, pons, and pyramids. The cer­ are dilated. (Phosphotungstic acid hematoxylin, X l). ebellar white matter is involved. 614 AJNR: 13, March/April1992

Fig. 4. Classical ALD. A, Coronal section with demyelination (decreased blue staining) and preservation of U fibers (arrowheads). 8, Unfixed coronal section of the occipital lobe with extensive demyelination and incomplete preservation of U fibers (arrowhead). (Loyez, X l).

Histologically, the cortex is normal. The blood vessels, beneath the pial surface, and changes are confined to white matter, which around the ependymal lining of the ventricles shows a complete loss of myelin, extensive as­ (Fig. 58). Accumulation of Rosenthal fibers trogliosis, and preservation of subcortical white around blood vessels may disrupt the blood-brain matter. In ALD, there is also a prominent inflam­ barrier, producing peri ventricular frontal en­ matory reaction with accumulation of perivascu­ hancement on CT (15) (Figs. 5C and 50). Disrup­ lar inflammatory cells. tion of the ependymal surface, particularly in the region of the aqueduct, leads to narrowing of the aqueduct and subsequent ventricular dilation. Alexander Disease Alexander disease is a reported in Canavan Disease infants, juveniles, and adults. No enzyme defect has been identified in this disorder. In infants, Canavan disease, or spongy degeneration of there is psychomotor retardation and megalen­ the nervous system, is an autosomal recessive cephaly often associated with , condition occurring in Jewish infants. Recently, , and seizures. Matalon ( 16) has described an At autopsy, the brain weight is increased and deficiency with N-acetyl aspartic aciduria in pa­ only on coronal sectioning is the soft, gray, often tients with Canavan disease. Typically, the onset collapsed white matter apparent, especially in the is in the first 6 months of life and is characterized frontal lobes (Fig. 5A). The cortex is usually white by apathy, loss of motor activity, and . and firm. The lateral and third ventricles may be Megalencephaly is conspicuous. The brain is dilated. The outlines of the basal ganglia are heavier than normal. On coronal sections, the sometimes indistinct but no gross abnormality of white matter is demyelinated, soft, gelatinous, brain stem, cerebellum, or spinal cord is apparent. and gray, with the texture of a wet sponge. In Microscopically, the diagnostic feature is a contrast to other leukodystrophies, the demyeli­ massive deposition of Rosenthal fibers composed nation of Canavan disease preferentially involves of dense intermediate glial fibrillary acidic protein the U fibers. The occipital lobes are more involved filaments confined to the cytoplasm of than the frontal and parietal lobes, which in turn (14). The Rosenthal fibers accumulate around are more affected than the temporal lobes. The AJNR: 13, March/April1992 615

A B

c D

Fig. 5. Alexander disease. A, Coronal section with prominent demyelination and focal cavitation (arrowheads). B, Ventricles are dilated due to secondary aqueductal stenosis (arrowhead) from proliferation of Rosenthal fibers . C, CT with frontal periventricular enhancement. D, Accumulation of red Rosenthal fibers (arrowheads) around blood vessels. (Hematoxylin and eosin, X 640). globus pallidus tends to be severely affected with mus, intermittent shaking movements of the the brain stem and spinal cord less involved. The head, , choreoathetoid movements, and cerebellum is atrophic (17). psychomotor retardation. Recently, Koeppen (18) Microscopically, there is prominent spongy found a severe deficiency of myelin lipids with a change with demyelination and proliferation of lack of proteolipid apoprotein (lipophilin). The astrogliosis (Fig. 6). Alzheimer-type II astrocytes genetic defect has been localized to the X chro­ are present. mosome ( 19). The brain and cerebellum are atrophic with large ventricles, normal cortex, patchy demyeli­ Pelizaeus-Merzbacher Disease nation, and variable astrogliosis. In the areas The classical form of Pelizaeus-Merzbacher dis­ around blood vessels, the myelin tends to be ease becomes clinically manifest in the first dec­ better preserved, creating a "tigroid" or "leopard­ ade of life. It is a slowly progressive X-linked skin" pattern of demyelination. Microscopically, recessive disorder that is characterized by nystag- there is evidence of demyelination with accumu- 616 AJNR: 13, March/ April 1992

tinguishing diagnostic features such as metachro­ matic substance seen in metachromatic leuko­ dystrophy, epithelioid cells see in Krabbe disease, Rosenthal fibers seen in Alexander disease, or spongy change seen in Canavan disease. As the biochemistry and molecular biology of these con­ ditions becomes clarified, these conditions will be moved out of the group of sudanophilic leuko­ dystrophies into a more specific and appropriate category.

Metabolic Disorders That Affect Gray and White Matter Most metabolic disorders affect gray and white matter, although one may be more affected than Fig. 6. Canavan disease. Prominent spongiosis of white matter the other. Those diseases where gray or white involving the U fibers. The gray-white matter junction (arrow­ heads) is at the top. (Hematoxylin and eosin, X 400). involvement is the predominant feature have al­ ready been discussed under those headings. In lation of lipid-laden macrophages. tends other conditions, gray and white matter are af­ to be well preserved (2). fected more equally. Disorders associated with defects of enzymes in mitochondria and peroxi­ somes best fit into this category. Not discussed Cockayne Syndrome are galactosemia, Menke disease, and Wilson disease, which also affect gray and white matter Cockayne syndrome occurs in late infancy, has (2). an autosomal recessive pattern of inheritance, and is associated with dwarfism, deafness, cata­ racts, retinal pigmentation, optic atrophy, thick­ Mitochondrial Disorders ened skull, and mental deficiency. No enzymatic Mitochondria are membranous cytoplasmic or­ defect has been discerned. ganelles that are bounded by an outer membrane On neuropathologic examination, the brain is and lined by a folded inner membrane (cristae). consistently small and the leptomeninges are dif­ Their number ranges from a few to several thou­ fusely thickened (20). The optic nerves are sand in each cell. Because mitochondria in living atrophic. Coronal section shows a gritty texture cells move and change their shape, the form seen correlating with the extensive calcification, espe­ by electron microscopy is highly variable. Their cially in the basal ganglia (Figs. 7 A and 78). The core is filled with a finely granular matrix. may be moderately dilated, Mitochondria trap chemical energy that is re­ with an atrophic cortical mantle and reduced leased by the oxidation of amino acids, fatty white matter. The cerebellum is also atrophic. acids, and glucose in a form, adenosine triphos­ Microscopically, there is a "leopard skin" pat­ phate (A TP), that is easily utilized by the cell. The tern of demyelination seen in the white matter major source of energy is glucose. Glycolytic (Fig. 7C) and there is cerebral calcification. In enzymes break down glucose to form pyruvic some areas, the calcification is in the vessel walls, acid which is then oxidized to acetyl coenzyme whereas, in other areas, the calcification appears A. Further oxidations through the Krebs' tricar­ to be unrelated to blood vessels (2). boxylic acid cycle (citric acid cycle) lead to the end products of carbon dioxide and water. Sudanophilic Leukody strophies Through the electron transfer system of cyto­ chromes, the energy released is chemically fixed The term sudanophilic leukodystrophies ap­ as ATP. The enzymes of the Krebs cycle and the plies to those leukodystrophies that cannot be cytochrome-electron transfer system are located classified in any other way radiologically, bio­ in the mitochondria. The energy stored in ATP is chemically, or pathologically (2 , 21). Pathologi­ later released by ATPases that lie in strategic cally, the pattern of demyelination is that of a locations throughout the cell, such as the cell dysmyelination process without evidence of dis- membrane (22, 23). AJNR: 13, March/Apri11992 617

A 8 Fig. 7. Cockayne syndrome. A, Coronal section showing patchy demyelination. 8 , Radiograph of frontal coronal section showing extensive calcification. C, "Leopard skin" pattern of demyelination is seen in the centrum ovale (, X1).

c

Clinical demonstration of lactic acidosis usually Pathologically, the patterns of damage in the focuses medical attention on the mitochondria. brain are related to cerebral infarction, often in Although the spectrum of clinical presentations the occipital lobes (MELAS), or to a more diffuse is wide (Table 3) and the degree of overlap is degenerative process occurring as an end stage significant, three syndromes of mitochondrial of mitochondrial dysfunction called Leigh disease dysfunction have emerged: myoclonic epilepsy or subacute necrotizing encephalomyelopathy. with ragged-red fibers (MERRF), mitochondrial Leigh disease is not caused by a single enzyme encephalopathy, lactic acidosis, and stroke-like defect; it can occur as a result of a defect of syndromes (MELAS), and Kearns-Sayre syn­ almost any of the mitochondrial enzymes (2). drome (KSS). The recognition of mitochondrial Leigh disease is characterized pathologically by diseases is relatively recent so that insight and spongiosis, demyelination, astrogliosis, and cap­ understanding of this group of disorders is in a illary proliferation with consistent anatomical in­ state of flux. Consistent reliable correlations be­ volvement of the (periaqueductal gray tween clinical syndromes, neuroimaging diag­ matter and substantia nigra), pons (tegmentum), noses, pathologic diagnoses, and biochemical de­ and mediJlla (tegmentum, cranial nerve nuclei in terminations have not been firmly established. the floor of the fourth ventricle and inferior olivary 618 AJNR: 13, March/April 1992

TABLE 3: Selected mitochondrial encephalopathies•

Manifestations MERRF MELAS KSS + + + + + + Short stature + + + Deafn ess + + + Lactic acidosis + + + Ragged-red fibers + + + Spongy degeneration + + +

Myoclonus + Seizures + + Ataxia + +

Vomiting + Blindness + Hemiparesis +

Ophthalmoplegia + Retinitis pigmentosa + A Heart block + Elevated CSF protein +

' Adapted from Di Mauro et al (22). Note.-+ = present; - = absent; CSF = cerebrospinal fluid ; for other abbreviations refer to text.

nuclei), cerebellum, basal ganglia, thalamus, and spinal cord (posterior columns) (Fig. 8A). A diagnosis of mitochondrial disorder is most convincingly established by a combination of consistent clinical, radiologic, pathologic, bio­ chemical, and molecular abnormalities. Since mi­ tochondrial abnormalities are usually generalized, a muscle biopsy is one of the early steps in the diagnostic process (24). In a positive muscle bi­ opsy, ragged-red fibers are demonstrated with a special stain: Gomori's modified trichrome (Fig. B 88). Electron microscopy has demonstrated a spectrum of mitochondrial abnormalities (Fig. 8C), with disturbances of mitochondrial number, size, shape, cristae patterns, and recognition of inclusions. The presence of morphologically ab­ normal mitochondria is an indication for exten­ sive biochemical and molecular investigation aimed at defining the precise enzymatic defect, so that this group of conditions can be under­ stood, enabling more effective treatment for the child.

Peroxisomal Disorders Enzyme deficiencies located in peroxisomes c have assumed importance only recently (25). Morphologically, peroxisomes have been de­ Fig. 8. Mitochondrial cytopathy. A, Periaqueductal demyeli­ nation (arrowhead) and spongiosis in Leigh disease. (Luxol fast scribed as microbodies measuring 0.2-1.0 ,urn blue, X4). B, Ragged-red fibers in muscle (arrowheads) (Gomori's and limited by a single membrane filled with a modified trichrome, X400). C, Abnormal mitochondria (arrow­ homogeneous matrix. A by definition heads). (Electron micrograph, X34,000). AJNR: 13, March/April 1992 619 contains a m1mmum of one oxidase to form TABLE 4: Peroxisomal disorders hydrogen peroxide and one catalase to decom­ Reduction of peroxisomal number and function pose it, but it may have more than 40 enzymes, Zell weger syndrome the nature of which depend on the cell type. Only Neonatal ALD some of the enzymatic defects of peroxisomes Infantile are related to well-defined clinical disorders (Table Hyperpipecolic acidemia Normal number of peroxisom es but decreased enzymatic activity 4). From a pathologic and neuroimaging point of Pseudo-Zellweger sy ndrome view, both neonatal ALD and Zellweger syndrome Rhizomelic chondrodysplasia punctata are of interest. Other syndromes will become Normal number of peroxisomes and single enzymatic defect better defined as insights into enzymatic defects Acatalasem ia develop. Sex-linked ALD In neonatal ALD, the striking findings are in white matter, where there is severe and almost complete loss of myelin from the centrum semi­ ovate. Neonatal ALD is similar to classical ALD in respect to the severity of demyelination and to the prominent involvement of the occipital lobes. Neonatal ALD is unlike classical ALD, in that it may show subtle polymicrogyric changes in the cortex (1). In peroxisomal disorders such as Zellweger syndrome, there is an unusual combination of abnormalities: neuronal migration, suggesting an effect of peroxisomal enzyme dysfunction on brain maturation, and an active process of de­ myelination consistent with an ongoing dysfunc­ tion of peroxisomes. In Zellweger syndrome, the gray matter shows A prominent polymicrogyria together with neuronal heterotopia, olivary dysplasia, and subependymal cysts (Fig. 9). The white matter shows mild de­ myelination and astrogliosis (26, 27). Other find­ ings in Zellweger syndrome include dysmorphic facies (high forehead, low nasal bridge, epicanthal folds), ocular findings (cataract, optic atrophy, retinitis pigmentosa), and calcific stippling of the patella.

Metabolic Neurologic Diseases with No Gross Neuropathology There are many metabolic disorders in which there are definite neurologic clinical manifesta­ tions but no apparent gross pathologic abnor­ 8 malities. Not surprisingly, these conditions may also appear normal on diagnostic neuroimaging. Fig. 9. Zellweger syndrome. A, Liver showing many mitochon­ These conditions include Lesch-Nyhan syn­ dria (a) and rare peroxisomes (b). (Electron micrograph, X40,000). drome; Wolman disease; Morquio syndrome; Sly 8 , The brain shows prominent polymicrogyria. disease; mucolipidosis I, II, Ill, IV; fucosidosis; mannosidosis; and others. In these conditions, the Conclusions defect lies at the neurotransmitter /biochemical The subject of metabolic disease is extremely level, interfering with cellular function but pre­ broad. Many disorders with precise enzyme de­ serving cell structure. fects have nonspecific and nondiagnostic pat- 620 AJNR: 13, March/April 1992

terns of pathology. A few have fairly character­ 8. Haltia T , Pa lo J , Haltia M , et al. Juven ile metachromatic leukodystro­ istic patterns. The gross patterns of neuropath­ phy: clinical, biochemical, and neuropathological studies in nine new cases. Arch Neurol1980;37:42-46 ology associated with lysosomal enzyme defects 9. Feanny ST, Chuang SH, Becker LE, et al. Intracerebral peri ventricular are cortical atrophy and leukodystrophy. Those hyperdensities: a new CT sign on Krabbe globoid cell leukodystrophy. associated with mitochondrial enzyme defects are J Inherited Met Dis 1987; 10:24-27 Leigh disease (periventricular demyelination and 10. Kobayashi T , Goto I, Yamanaka T , et al. Infantile and fetal globoid , basal ganglia spongiosis) and focal infarc­ cell leukodystrophy: analysis of and galactosyl­ . Ann Neurol1988;24:517-522 tion. The gross patterns of neuropathology as­ 11. Moser HW, Moser AB, Kawamura N, et al. Adrenoleukodystrophy: sociated with peroxisomal enzyme defects are studies of the phenotype, and biochemistry. Johns Hopkins polymicrogyria and leukodystrophy. However, as fried J 1980;147:217-224 we see more enzymatic variations of these rare 12. Tsuji S, Sano T , Argia T, et al. Increased synthesis of hexacosanoic disorders presenting at different stages of disease acid (C26:0) by cultured skin fibroblasts from patients with adreno­ leukodystrophy (ALD) and adrenomyeloneuropathy (AMN). J progression, even the known patterns become Biochem 1981 ;90: 1233-1240 less precise diagnostically and more suggestive 13. Singh I, Moser HW, Moser AB, et al. Adrenoleukodystrophy: impaired of a wide differential diagnosis. Because our un­ oxidation of long chain fatty acids in cultured skin fibroblasts and derstanding of the pathogenesis of many meta­ adrenal cortex. Biochem Biophys Res Commun 1981; 102:1223-1229 bolic disorders is still evolving, better correlation 14. Borrett D, Becker LE. 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